ABSTRACT
Indoleamine 2,3-Dioxygenase (IDO), is a speed limiting enzyme that catalyzes the decomposition and metabolism of Tryptophan along Tryptophan-IDO-Kynurenine pathway [1]. Tryptophan is a necessary amino acid for activating cell growth and metabolism. Additionally, the insufficiency of Tryptophan can lead to immune system dysfunction. Raising the level of Indoleamine 2,3-Dioxygenase protein can promote stagnation and apoptosis of effector T cells [2].In contrast, the decline in the number of effect T cells naturally protects cancer cells from attack. Therefore, Indoleamine 2,3-Dioxygenase is a potential target for tumour immunotherapy, such as melanoma, ovarian cancer, lung cancer, leukaemia, and so on, especially in solid tumours [3]. In the study, we have done sets of virtual screening aided by computer techniques in order to find potentially effective inhibitors of Indoleamine 2,3-Dioxygenase. Firstly, screening based on structure was carried out by Libdock. Then, ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction were also analyzed. Molecular docking and 3D-QSAR pharmacophore generation were used to study the mechanism of these compounds and Indoleamine 2,3-Dioxygenase's binding. A molecular dynamic analysis was carried out to assess if these potential compound's binding is stable enough. According to the results of the analysis above, two potential compounds (ZINC000012495022 and ZINC000003791817) from the ZINC database were discovered to interact with Indoleamine 2,3-Dioxygenase with appropriate energy and proved to be none toxic. The study offered valuable information of Indoleamine 2,3-Dioxygenase inhibitor-based drug discovery in cancer therapy by increasing the activity of T cells and releasing immunity suppression [4, 5].
Subject(s)
Antineoplastic Agents/pharmacology , Immunotherapy/methods , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Neoplasms/drug therapy , T-Lymphocytes, Cytotoxic/drug effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Apoptosis/immunology , Cell Line, Tumor , Crystallography, X-Ray , Drug Discovery , Female , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/ultrastructure , Kynurenine/metabolism , Male , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Neoplasms/immunology , Structure-Activity Relationship , T-Lymphocytes, Cytotoxic/immunology , Tryptophan/metabolism , Xenograft Model Antitumor AssaysABSTRACT
IDO1 (indoleamine 2, 3-dioxygenase 1), a well characterized immunosuppressive enzyme, has attracted growing attention as a potential target for cancer immunotherapy. Hydroxylamidine compounds INCB024360 and INCB14943 (INCB024360 analogue) are highly effective IDO1 inhibitors. INCB024360 is undergoing clinical trials for treatment of various types of human cancer. Here, we determined the co-crystal structure of IDO1 and INCB14943, and elucidate the detailed binding mode. INCB14943 binds to heme iron in IDO1 protein through the oxime nitrogen. Further analysis also reveals that a halogen bonding interaction between the chlorine atom (3-Cl) of INCB14943 and the sulphur atom of C129 significantly improves the inhibition activity against IDO1. Comparing with the other reported inhibitors, the oxime nitrogen and halogen bond interaction are identified as the unique features of INCB14943 among the IDO1 inhibitors. Thus, our study provides novel insights into the interaction between a small molecule inhibitor INCB14943 and IDO1 protein. The structural information will facilitate future IDO1 inhibitor design.
Subject(s)
Hydroxylamines/chemistry , Indoleamine-Pyrrole 2,3,-Dioxygenase/chemistry , Indoleamine-Pyrrole 2,3,-Dioxygenase/ultrastructure , Oxadiazoles/chemistry , Oximes/chemistry , Binding Sites , Enzyme Activation , Protein Binding , Protein Conformation , Structure-Activity RelationshipABSTRACT
Multiple-scattering (MS) analysis of EXAFS data on met-indoleamine 2,3-dioxygenase-2 (IDO2) and analysis of XANES have provided the first direct structural information about the axial donor ligands of the iron center for this recently discovered protein. At 10K, it exists in a low-spin bis(His) form with Fe-Np(av)=1.97Å, the Fe-NIm bond lengths of 2.11Å and 2.05Å, which is in equilibrium with a high-spin form at room temperature. The bond distances in the low-spin form are consistent with other low-spin hemeproteins, as is the XANES spectrum, which is closer to that of the low-spin met-Lb than that of the high-spin met-Mb. The potential physiological role of this spin equilibrium is discussed.
